Preparation of 5alpha-bromo-6beta-hydroxy steroids



United States Patent 3,146,245 PREPARATION OF Sa-BROMO-Gfi-HYDROXYSTEROIDS Johannes Andreas Hanegraaf, Oss, Netherlands, assignor toOrganon Inc., West Orange, N.J., a corporation of New Jersey No Drawing.Filed Sept. 3, 1963, Ser. No. 306,328 Claims priority, applicationNetherlands Sept. 25, 1962 2 Claims. 01. 260-3974) The invention relatesto a process for the preparation of a-bromo-Gfl-hydroxy-steroids byreaction of a A steroid with hypobromous acid or a hypobromous acidproviding agent in the presence of an organic solvent.

It is known that unsaturated steroids can be converted into thecorresponding bromohydrine compounds with hypobromous acid, thusstarting from a M -steroid a '9ot-bromo-l-lB-hydroxy compound isobtained and starting from a A -steroid the correspondingSa-bromo-Gfl-hydroxy compound.

Especially the last few years last-mentioned group of bromohydrinecompounds has become most important in connection with the developmentof a new method for the preparation of l9-nor-steroids. For untilrecently 19- nor-steroids were prepared by dehydrogenation of A -3-keto-steroids in 1,2-position, aromatization of the resulting A-3-keto-steroids, followed by conversion of the resulting A-3-hydroxy-steroids into A -3-keto-19- nor-steroids, such as1'9-nor-testosterone, the 17-alkyl derivatives thereof,19-nor-progesterone and the like, by reduction after etherification in3-position.

A better method for the preparation of 19-nor-steroids consists in that6fi-hydroxy-10-methyl-steroids are converted into 6,19-0xide-steroids byoxidation with a metal acylate, whereupon the 6,19-oxido ring is openedby reduction to obtain l9-hydroxy-steroids, which after a possiblypreceding oxidation of the 19-hydroxyl group are converted into19-nor-steroids by treatment with a strong base.

The 6B-hydroxy-steroids to be applied as starting products in thisprocess can now be prepared in an efiicient manner from A -steroids byconversion of the latter into the corresponding 5a-bromo-6fl-hydroxycompounds by means of hypobromous acid by any method known per se. Thefact that these starting products have a bromine atom in 5-position isin most cases a great asset, because most of the biologically active19-nor-steroids have a double bond between the carbon atoms 4 and 5, or5 and 6, and such a bond can be very easily introduced bydehydrobromination of the Sa-bromc-steroid.

According to the methods described in the literature5a-bromo-6fl-hydroxy-steroids are prepared by reacting A -steroids withhypobromous acid or hypobromous acid providing agents, the reactionbeing preferably performed in the presence of a strong acid, such asperchloride acid.

These known conversions are performed in the presence of dioxane assolvent. Experimental investigations have shown that performed in thismanner the present reaction yields at best 70 to 75% by weight only. Onapplication of other solvents, such as alcohols, especially tertiaryalcohols, even lower yields were obtained, while others, such as ketonesor ethyl acetate gave at best a slight improvement in the yield ascompared with dioxane (75 to 80% Surprisingly it has been found now thatwhen the present reaction is performed in an aliphatic ether as solventa considerable improvement is obtained in the yield. Generally yields ofbromohydrine compounds vary now from 95 to 100 percent by weight, whichmeans an increase of about 20% or more relating to the common solvents.

3,146,245 Patented Aug. 25, 1964 ICC.

Generally ethers can be applied indicated by the general formula:

R O-R in which R and R represent an aliphatic hydrocarbon chain with 1-6carbon atoms.

As examples of ethers to be applied are mentioned: dimethyl ether,diethyl ether, methylethyl ether, di-isopropyl ether, di-isobutyl ether,butylmethyl ether, etc. Usually diethyl ether is used as solvent.

The addition of hypobromous acid to A -steroids can be performed bydissolving the relative steroid in an aliphatic ether, addinghypobromous acid or a hypobromous acid providing agent to it in thepresence of water.

As hypobromous acid providing agents are mentioned: N-bromo-derivativesof lower aliphatic carboxylic acid amides or imides, such asN-bromoacetamide and N- bromosuccinimide or other compounds, such asdibromodimethyl hydantoin. For preference N-bromoacetamide is applied.The reaction is usually performed in the presence of a strong acid, suchas perchloric acid or sulphuric acid. The former is preferred.

The reaction period and reaction temperature are not tied to strictlimits, but the reaction is usually performed in 10 to 60 minutes at atemperature varying between 0 and boiling point of the solvent.

The concentration of the steroid solution, too, is not very importanteither. Favourable results were obtained with 5 to ml. of ether per 1gm. of steroid.

The invention is illustrated further by the following examples:

Example I To a suspension of 10 gm. of A-3fi,l7-dihydroxyandrostene-B-acetate-17benzoate in ml. of diethyl etherare added 3.5 gm. of N-bromoacetamide and a mixture of 4 ml. ofperchloric acid and 10 ml. of Water, after which the reaction mixture isstirred for 20 minutes at 20 C. The reaction is decomposed by theaddition of a solution of sodium sulfite, after which the ether layer isseparated, washed with a solution of 5% sodium sulfite, water, asolution of 5% sodium bicarbonate and next with water until neutral.Next the solution of ether is dried on sodium sulfate and thenevaporated to dryness in vacuo. The residue is recrystallized from amixture of acetone and hexane to obtain the 3 3,6;3,l7,8-trihydroxy-5a-bromo-androstane-3-acetate-17-benzoate in a yield of 100% by weight.Melting point=153l56 C. (under decomposition) The conversion describedbefore was also performed in some so far conventional solvents.

The results of these comparative tests were as follows: (a) Solvent:dioxane. Yield: 71% by Weight.

(b) Solvent: t-butanol. Yield: 62% by weight. (c) Solvent: ethylacetate.Yield: 72% by weight.

Example 11 One hundred grams of A -3B,l7p-diacetoxy-androstene aresuspended in 1500 ml. of methylethylether and cooled to 17 C. Next 35gm. of N-bromoacetamide are added to this mixture and then a mixture of40 ml. of perchloric acid and 100 ml. of water.

The mixture is stirred for 15 minutes at 20 C., whereupon the reactionis decomposed by the addition of sodium sulfite.

After working up and crystallisation as described in Example I, the3,8,65,l7B-trihydroxy-Son-bromo-androstane-3,17-diacetate is obtained ina yield of 97.5% by weight. The same result was obtained usingN-bromosnccinimide.

In the same manner the A -3/3-acetoxy-l7fi-benzoxyandrostene isconverted into the corresponding Sat-bromo- 6fl-hydroxy compound in ayield of 94.5% by weight by application of di-isopropyl ether.

Example 111 To a suspension of 100 gm. of A -3/3-acet0Xy-17-ket0-androstene in 1250 ml. of dimethyl ether are added at 15 C. 35 gm. ofN-bromoacetamide, 20 m1. of perchloric acid and 50 ml. of water, afterwhich the reaction mixture is stirred for 20 minutes at 18 C. Next themixture is treated further by the process described in Example I toobtain the 3/3,6B-dihydroxy-5a-bromo-17- keto-androstane-3-acetate in ayield of 96% by weight.

Example IV A mixture of 12 gm. of A -3B-acetoxy-20-keto-pregnene, 240m1. of diethyl ether, 4.2 gm. of N-bromo acetamide, 5 ml. of perchloricacid and 12 ml. of Water are stirred for 35 minutes at room temperature,after which the mixture is worked up by the process described in ExampleI to obtain the 3B-6B-dihydroxy-5a-bromo- 20-keto-pregnane-3-acetate ina yield of 93.5% by weight.

I claim:

1. In the process for the preparation of 5a-bromo-6phydroxy steroids bythe reaction of a A -steroid with a compound selected from the groupconsisting of hypobromous acid and a hypobromous acid providing agent inthe presence of an organic solvent, the improvement which comprisesperforming said reaction in a saturated aliphatic ether of the formula:

R OR in which R and R represent aliphatic hydrocarbon radicalscontaining from 1 to 6 carbon atoms.

2. The process of claim 1 in which the aliphatic ether is diethyl ether.

No references cited.

1. IN THE PROCESS FOR THE PREPARATION OF 5A-BROMO-6BHYDROXY STEROIDS BYTHE REACTION OF A $5-STEROID WITH A COMPOUND SELECTED FROM THE GROUPCONSISTING OF HYPOBROMOUS ACID AND A HYPOBROMOUS ACID PROVIDING AGENT INTHE PRESENCE OF AN ORGANIC SOLVENT, THE IMPROVEMENT WHICH COMPRISESPERFORMING SAID REACTION IN A SATURATED ALIPHATIC ETHER OF THE FORMULA: